Association of two genomic variants with HPV subtype-specific risk of cervical cancer

Problem: Human papillomavirus infection is integral to developing invasive cervical cancer in the majority of patients. It is unclear how genetic susceptibility to HPV infection directs cervical disease development by affecting host immune response. In a recent genome-wide association study, rs9357152 and rs4243652 have been associated with seropositivity for HPV16 or HPV18, respectively. Methods: We investigate whether the two HPV susceptibility variants show association with subtype-specific cervical cancer in a genetic case-control study (rs9357152: N =560, N = 334; rs4243652: N = 544, N = 115). We further tested whether rs9357152 modulates gene expression of any of 36 genes at the human leukocyte antigen locus in 257 cervical tissues. Results: rs9357152 was associated with invasive HPV16+ve cancer (OR 1.30, 95% CI 1.01-1.66, P= 0.04) whereas rs4243652 was associated with HPV18+ve adenocarcinomas (OR=2.71, 95% CI=1.09-6.75, P= 0.03). rs9357152 was found to be an eQTL for HLA-DRB1 in HPV positive tissues (p =0.0009), with the risk allele lowering mRNA levels. Conclusions: HPV seropositivity variants at chromosome 6 and 14 modulate subtype-specific cervical cancer risk. rs9357152 may exert its effect through regulating HLA-DRB1 in the presence of HPV.